Cancer is a major health problem across the globe and the conquest of cancer poses great challenges to medical science. Chemotherapy is one of the major modalities for cancer therapy and generally refers to the treatment of cancer with the use of one or more anti-cancer agents (chemotherapeutic agents). Some chemotherapeutic agents are also used to treat other diseases and conditions, such as arthritis, systemic lupus erythematosus, AL amyloidosis, ankylosing spondylitis, multiple sclerosis, Crohn's disease, psoriasis, and scleroderma.
Many anti-cancer agents act by impairing mitosis and thereby target rapidly-dividing cells, a hallmark property of most cancer cells. Some agents stop the cells from dividing and others kill the cells, e.g. by triggering apoptosis. Certain newer agents (e.g., various monoclonal antibodies) are being developed to provide a more targeted therapy (as distinct from traditional chemotherapy), for example, those targeting specific proteins that are over expressed in certain types of cancer cells and essential for their growth. Such treatments are often used in combination with traditional chemotherapeutic agents in antineoplastic treatment regimens.
Chemotherapy may employ one anti-cancer agent at a time (single-agent chemotherapy or mono-chemotherapy) or multiple agents at once (combination chemotherapy). Chemical agents that enhance the radiosensitivity of cancer to radiation therapy (ionizing radiation) are called radiosensitizers. Treatment using chemical substances (called photosensitizers) that convert to cytotoxic activity only upon exposure to light is called photodynamic therapy.
While a variety of anti-cancer agents are available, nearly all are toxic. Chemotherapy generally causes significant, and often dangerous, side effects, including kidney toxicity, liver toxicity, severe nausea and vomiting, bone marrow depression, myelosuppresion/immunosuppression, mucositis (inflammation of the lining of the digestive tract), alopecia (hair loss), cytopenia, pain and fatigue. Additional side-effects can include cachexia, cutaneous complications, such as hypersensitivity reactions, as well as neurological, pulmonary, cardiac, reproductive and endocrine complications. Side effects associated with anti-cancer agents are generally the major factor in defining a dose-limiting toxicity (DLT) for the agent. Managing the adverse side effects induced by chemotherapy is of major and critical importance in the clinical management of cancer treatment. In addition, many tumor cells are resistant, or develop resistance, to anti-cancer agents, e.g. through multi-drug resistance.
Cisplatin (cis-Pt(NH3)2Cl2) is a platinum-based antineoplastic drug and is one of the most widely used drugs for cancer treatment. Cisplatin has also been used as a radiosensitizer to enhance the radiosensitivity of cancer cells to ionizing radiation [Rose et al., 1999]. Despite its widespread use, cisplatin has two major drawbacks: severe toxic side effects and both intrinsic and acquired resistance. These drawbacks even led to a call for terminating the clinical applications of heavy-metal Pt-based anticancer drugs [Reese, 1995]. There remains a need to identify less toxic analogues that reduce cisplatin toxicity and/or prevent or overcome drug resistance.
Despite increasing costs to pharmaceutical companies, the number of truly innovative new medicines approved by the US Food and Drug Administration and other major regulatory bodies around the world has been decreasing over the past decade. The identification of new anti-cancer agents remains a somewhat empirical process, generally involving screening a large number of compounds in order to identify a very small number of potential candidate molecules for further investigation. Thus, there is a need for a more rational and efficient approach to the design of novel anti-cancer agents. While various drug discovery tools are available, such as binding-based screening, inhibitor-based screening and structure-based drug design, an outstanding problem has been lack of understanding of the precise molecular mechanisms of action of most anticancer drugs currently in use or in clinical trials. Without a specific mechanistic understanding, it is difficult to learn from the successes and failures of individual therapies. Thus, the search for new anticancer drugs by traditional methods has proven to be expensive, difficult and inefficient. There is a compelling need for innovative cancer research focusing on a much deeper understanding of fundamental mechanisms of DNA damage/repair, apoptosis, tumorigenesis, and therapy in molecular terms in order to ultimately conquer cancer [Varmus, 2006; Alberts, 2008, 2011], which in turn will enable breakthroughs in cancer therapy.
Direct observation of molecular reactions is of great importance in diverse fields from chemistry and biology to medicine. Femtosecond (fs) (1 fs=10−15 s) time-resolved laser spectroscopy (fs-TRLS) is a direct technique to visualize molecular reactions in real time. Its key strength lies in short duration laser flashes of a time scale at which many molecular reactions truly occur. Its application to chemical and biological systems gave birth to new fields of femtochemistry and femtobiology [Zewail, 2000].
Over the past decade, the inventor has coined an emerging transdisciplinary frontier, femtomedicine (FMD), which involves a fusion of ultrafast laser techniques with biomedical sciences to advance fundamental understanding and therapies of major human diseases [Lu, 2010]. Indeed, femtomedicine holds the promise of accelerating discovery and new advances in therapies of major human diseases, notably cancer.
FMD studies by the inventor have led to the discoveries of a reductive damaging mechanism in the cell, which may be closely related to human diseases notably cancer [Lu et al., 2013], and a dissociative electron transfer (DET) reaction mechanism of cisplatin as both an anti-cancer drug and a radiosensitizer in combination with radiotherapy [Lu, 2007; Lu et al., 2007; Lu, 2010]. These mechanistic understandings provide opportunities to improve the therapies of existing drugs and to develop new effective drugs.
PCT/CA2013/051005 (to the present inventor), entitled Radiosensitizer Compounds for Use in Combination With Radiation, discloses a class of non-platinum based compounds in combination with radiation therapy, using ionizing radiation, to enhance the anti-cancer efficacy of radiotherapy. The compounds were shown to enhance the radiosensitivity of cancer cells to ionizing radiation (also see, Lu, 2014).